Abstract

Braz J Med Biol Res, May 1997, Volume 30(5) 561-575

Photochemistry and photobiology of actinic erythema: defensive and reparative cutaneous mechanisms

A.C. Tedesco¹, L. Martínez² and S. González²

¹Departamento de Química, Faculdade de Filosofia, Ciências e Letras, Universidade de São Paulo, 14040-901 Ribeirão Preto, SP, Brasil

²Wellman Laboratories of Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA

^Text

Correspondence and Footnotes ^{Correspondence and Footnotes} Correspondence and Footnotes

Abstract

Sunlight is part of our everyday life and most people accept it as beneficial to our health. With the advance of our knowledge in cutaneous photochemistry, photobiology and photomedicine over the past four decades, the terrestrial solar radiation has become a concern of dermatologists and is considered to be a major damaging environmental factor for our skin. Most photobiological effects (e.g., sunburn, suntanning, local and systemic immunosuppression, photoaging or dermatoheliosis, skin cancer and precancer, etc.) are attributed to ultraviolet radiation (UVR) and more particularly to UVB radiation (290-320 nm). UVA radiation (320-400 nm) also plays an important role in the induction of erythema by the photosensitized generation of reactive oxygen species (singlet oxygen (¹O₂), superoxide (O₂^.-) and hydroxyl radicals (^.OH)) that damage DNA and cellular membranes, and promote carcinogenesis and the changes associated with photoaging. Therefore, research efforts have been directed at a better photochemical and photobiological understanding of the so-called sunburn reaction, actinic or solar erythema. To survive the insults of actinic damage, the skin appears to have different intrinsic defensive mechanisms, among which antioxidants (enzymatic and non-enzymatic systems) play a pivotal role. In this paper, we will review the basic aspects of the action of UVR on the skin: a) photochemical reactions resulting from photon absorption by endogenous chromophores; b) the lipid peroxidation phenomenon, and c) intrinsic defensive cutaneous mechanisms (antioxidant systems). The last section will cover the inflammatory response including mediator release after cutaneous UVR exposure and adhesion molecule expression.

Key words: sunburn, antioxidant, DNA photodamage, reactive oxygen species, UV radiation

The sun emits electromagnetic radiation over a wide range of wavelengths that include the ultraviolet (200-400 nm), visible (400-760 nm) and the near- and far-infrared regions (>800 nm) (1). The damage to the ozone layer, an effective barrier against the penetration of ultraviolet radiation to the earth, has had a tremendous impact on interest in the study of the potentially damaging effects of UV light on different organisms, man among them (2,3). Single or multiple exposures to solar radiation without appropriate protection can produce a variety of unwanted effects that are of interest to the physician, especially the dermatologist. These effects are the result of acute and chronic photobiological responses that are in turn a consequence of photochemical reactions such as those listed in Table 1 (4,5).

The basic cutaneous response resulting from exposure to solar radiation is the actinic erythema or "sunburn" which appears 3 to 4 h after exposure and can last 5 to 6 days depending on the intensity (6). Other signs and symptoms include skin sensitivity to touch, as well as edema, discomfort and pain. Delayed pigmentation or tanning begins after the second or third day and, finally, after a period of 6 to 10 days peeling can occur (7,8).

The photobiological effects of ultraviolet radiation show that the UVB components (290-320 nm) in particular are erythematogenic and carcinogenic, and induce photoaging and direct damage to DNA, RNA, proteins and other cell constituents. Nonetheless, UVA radiation (320-400 nm) also plays an important role in the induction of erythema by the photosensitized generation of reactive oxygen species (ROS), such as singlet oxygen (¹O₂) or the superoxide (O₂^{. -}) and hydroxyl radicals (^.OH) that damage DNA and cell membranes, and promote carcinogenesis and the changes associated with photoaging (9). Therefore, both the UVA and UVB components trigger this acute inflammatory response which appears in the form of erythema.

The characteristics associated with the erythema induced by exposure to radiation under laboratory conditions depend on both the intensity and dose of the wavelength used (10-12). UVC (200-290 nm)-induced erythema is the least intense and disappears after a couple of hours, but the erythema induced by UVB and UVA radiation can persist for days since these components penetrate deeper into the skin (13-15). It should be emphasized that even though UVB radiation is more erythematogenic than UVA (the minimal dose required at 297 nm for the erythema response is 1250 times higher than at 365 nm) (16,17) more photons in the UVA region reach the earth's surface (10-100-fold higher for UVA than UVB). Table 2 lists the major reactions induced by the different wavelength ranges of solar radiation.

The histological changes occurring in the skin after exposure also depend on the wavelength of the radiation. These changes may be preceded by the appearance of diskeratotic cells and a reduction in the number of Langerhans cells in the case of UVB exposure (González S, Malallah YH and Johnson B, unpublished data). For UVA radiation, the histopathological changes are fundamentally restricted to the dermis and depend largely on the presence of photosensitizers (Table 3). However, recent studies by Lavker et al. (18) in humans have shown that chronic exposure to UV radiation at sub-erythematogenic doses may also induce the appearance of diskeratotic cells and a reduction in the number of Langerhans cells.

In this review we will focus on erythema as an inflammatory response after exposure to ultraviolet radiation, when the absorption of photons by chromophores in the skin promotes a series of photochemical reactions responsible for this response. First, we will discuss the nature of these reactions, i.e., the production of free radicals and ROS. Several processes will be described, such as lipid peroxidation and its possible role as an initiating mechanism in the photoinduced damage. Also, the antioxidant systems present in the organism as means of protection will be discussed. Finally, we will discuss the biochemical alterations describing the different mediators implicated such as products of arachidonic acid, histamine, cytokines and neuropeptides. These mediators released by keratinocytes and other cutaneous cells, along with the expression of adhesion molecules on their surface, are of fundamental importance for leukocyte adhesion and the onset of the inflammatory response.

Photochemistry of UV-induced erythema: Studies on free radical generation and the production of ROS

The photoinduced inflammatory response is the result of a series of photochemical reactions taking place after the absorption of non-ionizing radiation by skin chromophores, each of them possessing a different absorption spectrum. At room temperature, most of the molecules are present in their ground state and as a result of absorption of radiation of a given energy (or of a specific wavelength) they undergo an electronic transition to an excited state. The nature of this excited state can be a singlet (if all the electrons have their spins paired) or a triplet (when there is an unpaired electron). Depending on the chromophore and on its environment, the lifetimes of these states can range from picoseconds or nanoseconds (for singlets) to microseconds (for triplets), and these lifetimes can be long enough to permit reactions to occur from these excited states resulting in chemical changes that generate different photoproducts known as free radicals or ROS. It is now well established that both species are continuously produced in vivo. Oxygen radicals can induce a number of disruptive cellular processes, including lipid peroxidation, DNA cleavage, altered enzyme activity, polysaccharide polymerization, and cell death. Because the production of radicals is a physiological process, the cells have developed several mechanisms to minimize the effects of these oxyradicals. The organism possesses relatively small molecules (a-tocopherol, ß-carotene, ascorbic acid, etc.) as well as more complex enzymatic systems (superoxide dismutase, catalase, thioredoxin reductase, glutathione peroxidase and reductase) for antioxidant purposes. Most of these UV light-induced cutaneous pathologies will be discussed later in this review.

There is a dose-response relation between the UV-induced erythema and the wavelength of irradiation. Solar radiation of shorter wavelength (UVB region, 290-320 nm) results in both epidermal and dermal changes. However, most UVB is absorbed by chromophores localized mainly in the epidermis, such as nucleic acids, amino acids, urocanic acid and melanin. Many of the chromophores act as protective agents against UV radiation. Melanin is the main chromophore in the epidermis absorbing photons of wavelengths ranging from 350 to 1200 nm.

The degree of the skin response to ultraviolet radiation depends on the localization and distribution of the chromophore as well as on skin thickness. Figures 1-5 summarize the photochemical reactions occurring when skin chromophores absorb UV radiation.

Of great photobiological interest (19,20) are the chemical changes of amino acids absorbing ultraviolet radiation. Tyrosine and tryptophan are the most common aromatic amino acids absorbing in the UVB region. At physiological pH, tryptophan (Trp) has an absorption maximum at 290 nm. Upon photon absorption, one of the reactions from the singlet excited state (Trp(S₁)) involves photoionization and the generation of the tryptophan radical cation (Trp^.+). The photoejected electron can react with molecular oxygen (³O₂) forming the superoxide radical anion (O₂^.-). This reactive oxygen species commonly dismutates to form hydrogen peroxide, H₂O₂,and, in the presence of catalytic amounts of copper or iron metalloions (Haber-Weiss/Fenton reactions), can generate the hydroxy radical ^.OH that can produce damaging effects on biological systems. Trp(S₁) can also undergo intersystem crossing to its triplet state (Trp(T₁)) and react with ³O₂ generating organic peroxyl radicals (^.TrpOO^.). Trp(T₁) can also generate ¹O₂ through a type II reaction (i.e., energy transfer, see Figure 1).

It is commonly accepted that even if tyrosine (Tyr) absorbs radiation in the UV region it ultimately transfers the absorbed energy to tryptophan residues in proteins (20). In vitro studies have demonstrated that the 254 run photolysis of Tyr yields dopamine as one of the main photoproducts (21). After a complex series of reactions, polymerization to melanin occurs (Figure 2).

The nitrogen bases are the main chromophores in nucleic acids capable of absorbing ultraviolet radiation in the 250-270 nm range. Photochemical alterations in nucleic acids have a major impact at the cellular level, leading to cell death, mutagenesis and photocarcinogenesis.

A variety of photoproducts have been identified (22-25), with the cyclobutyldimers and photohydrates of the pyrimidine bases being formed at higher levels (Figure 3). The formation and yields of these products vary both with the nature of the base and the sequence in the nucleic acid strand. Cyclobutyldimers between adjacent thymines are produced at higher yields than any other pyrimidine combination and so are the cytosine photohydrates. Another product involving covalent coupling of two pyrimidine bases is the pyrimidine-(6-4)-pyrimidone photoadduct, formed in greater yields in thymine-cytosine sequences. Early observations have demonstrated that purine nucleic acid components and particularly guanine, as the free base or the related nucleoside and nucleotides, are more readily photooxidized by a variety of photosensitizers than are their pyrimidine analogs. Figure 5 shows the guanine radical intermediates from type I photoreactions and from the ^.OH reaction giving rise to identical decomposition products. Guanine can also be attacked by singlet oxygen in a type II photoreaction. These radical intermediates can be employed as a diagnostic tool for the assessment of photooxidative damage to DNA.

The cell possesses specific enzymes capable of repairing some of these photoproducts (i.e., endonucleases) and loss of activity of these enzymatic systems (i.e., xeroderma pigmentosum) increases the likelihood that damage will persist in the genetic material after UV exposure.

Urocanic acid (UA), a deaminated histidine, is the main chromophore absorbing UV radiation in the stratum corneum. It is produced by the action of the enzyme histidase on the amino acid histidine. The absence of urocanase in the epidermis prevents the transformation of UA into the imidazolone propionic acid. Several investigators (26-28) have suggested that UA is a natural sun block since its absorption spectrum covers the region from 240-300 nm (maximum at 275 nm) overlapping the main erythematogenic region (i.e., 290-310 nm). The trans-isomer of UA is naturally present in the skin and after absorption of photons undergoes photoisomerization to the cis-isomer (Figure 4) which mimics several of the immunomodulatory effects of UV radiation.

The majority of the reactive species generated by the action of UV radiation on skin chromophores are radicals. Free radicals are, by definition, chemically active species which possess an unpaired electron in their orbitals. Biological systems are usually exposed to different types of radicals generated either endogenously or as a result of some exogenous injury. Radicals can undergo addition or electron-transfer reactions with different cellular components and have thus been implicated in the ethiopathogenesis of several diseases.

Free radicals can be neutral or charged species. An example of a neutral radical is the thyoil radical (RS^.) that can be produced by direct H-atom abstraction from a thiol group by another organic radical. This radical can be generated by the activation of thioredoxin reductase, an enzymatic antioxidant system (29). This epidermal membrane-associated free radical scavenging system that catalyzes the reduction of oxygen radicals to peroxide, although widely distributed in a variety of organisms and tissues, and located preferentially on the outer membrane surface in human epidermis, may be the first line of defense against free radical production induced by UV. The thioredoxin reductase/thioredoxin system has been implicated in a number of other antioxidant reactions (29).

Pyridinyl radicals are radical cations (i.e., positively charged radicals) which are involved in the formation of the chemical structure of two important coenzymes, NAD⁺ and NADP⁺ (30). The best known negatively charged radical is the oxyradical O₂^.-. The superoxide radical anion can be generated by different compounds and physical agents, such as ionizing radiation, ultraviolet radiation, hyperbaric oxygen and photosensitizing agents (31,32).

Although most of the oxygen consumed during cellular respiration is reduced to water by cytochrome C oxidase (33), a small amount of oxygen undergoes sequential stepwise univalent reduction and this is enough to produce a sufficient quantity of the superoxide radical and, ultimately, different ROS. These reactive species affect a variety of biological processes by damaging cellular membranes, enzymes, lipids, nucleic acids, and mitochondria by affecting the electron-transport chain. Among many processes that contribute to the generation of ROS are 1) the autooxidation of metabolites such as hydroquinones, thiols, hemoglobin (34), and catecholamines (33); 2) the enzymatic oxidation mediated by xanthine oxidase (35), aldehyde oxidase and orto-hydrodehydrogenase (31), and 3) the autooxidation of reduced species of the electron-transport chain generated from organelles such as mitochondria, microsomes or nuclei (36-38).

Oxidative stress may be regarded as an imbalance between the production of free radicals and their defense mechanisms. Such inefficiency of defense mechanisms may be due either to their relative deficit or inaccessibility or to their exhaustion following excess free radical production. Oxidative stress can be prevented or repaired by interventions that antagonize metabolic pathways of free radical generation, or that emulate or amplify physiological defense mechanisms. This toxic effect generated by hyperoxia or the inappropriate metabolism of oxygen is a well-defined cause of toxicity in biological systems. Most of the ROS generated after exposure of the skin to solar radiation (39-41) have a relatively short lifetime. Cellular injury caused by ROS involves generation of superoxide anion and hydrogen peroxide, but the most reactive mediator of such damage, however, appears to be the hydroxyl radical. Hydrogen peroxide is produced directly by a variety of oxidases and is also produced by dismutation of the superoxide anion (42-44).

This molecule must be considered dangerous because its small size and lack of charge allow it to diffuse across biological membranes and then, by reduction of H₂O₂ mediated by catalytic amounts of metal cations such as iron or copper in a reaction called iron-catalyzed Haber-Weiss reaction or sometimes Fenton reaction, produces OH^- and ^.OH (32,43,45). The relevant reactions are:

Another reactive oxygen species formed from molecular oxygen is ¹O₂. In biological systems, ¹O₂ is generated by absorption of incident light of specific wavelengths by excitable endogenous or exogenous molecules known as photosensitizers. This type of photosensitization is known as type II (46,47). A large number of sensitizers occur naturally in organisms (riboflavin, 4-thiouridine and 2-thiouracil, bilirubin, etc.), but many others need to be added exogenously to the system. The energy of the triplet excited state for the sensitizers is then transferred to an adjacent triplet (unexcited) oxygen molecule, raising molecular oxygen to the singlet oxygen. There are two excited states of ¹O₂ of 23 and 37 kcal, the latter having the shorter lifetime. Even if the energy of the photons in the ultraviolet and visible regions is enough to generate singlet oxygen, O₂ does not absorb at these wavelengths; therefore, ¹O₂ can only be generated, as established before, by an energy-transfer mechanism involving O₂. This mechanism constitutes the underlying principle of photodynamic therapy (PDT). In PDT, an exogenous chromophore (i.e., usually a photosensitizing dye) is taken up by the cell and irradiated with light of a specific wavelength usually corresponding to the wavelength of maximum absorption of the dye (48,49). The excited sensitizer transfers the absorbed energy to O₂, generating ¹O₂ and returning to its ground electronic state. ¹O₂ then reacts with different molecules through a series of complex biochemical reactions in different cellular components (DNA, membrane lipids, proteins, etc.), triggering the destruction and necrosis of neoplastic tissue.

Enzyme generation of ¹O₂ has been detected by IR spectroscopy and luminescence emission at 1268 nm from enzyme systems such as chloroperoxidase-H₂O₂-Cl^-, lactoperoxidase-H₂O₂-Br^-, and cyclooxygenase (50-55). This was the first direct experimental confirmation of ¹O₂ being produced as a chemical reactantgenerated by dark enzymatic systems, although this possibility has been critically discussed in the literature (56,57). As noted by Kanofsky (51), this biochemical production of ¹O₂ "should not be uncritically extrapolated to living systems".

Lipid peroxidation: initiating event in photooxidative stress

We have already discussed the different ROS generated after exposure of the skin to solar UV radiation (39-41) which have relatively short lifetimes. Biological membranes that are rich in polyunsaturated fatty acids (PUFA) (58) are vulnerable targets for free radical attack, especially by hydroxyl radicals produced in the Fenton reaction.

The hydroxyl radical reacts with methylene groups of unsaturated lipids by H-atom abstraction producing a lipid radical (L^.) which in a reaction with O₂ forms the lipid peroxyl radical (LOO^.). This LOO^. radical can react with another methylene group of another unsaturated fatty acid generating a lipid peroxide (LOOH) and another L^. which in the presence of metal ions forms alkoxy (LO^.) and peroxyl radicals.

Lipid peroxide generated by oxidative stress of UV light in the skin (58,59) has been known to be potentially deleterious for cellular function, having cytotoxic effects, stimulatory or inhibitory effects on enzymes, and cell membrane damage and carcinogenic effects. Recent observations (60) indicate that the serum levels of lipid peroxide after cutaneous exposure to UVB radiation reach a maximum 18 h later, decreasing during the next 2 or 3 days.

Black and associates (61) have emphasized the observation that irradiation of the skin both in vitro and in vivo leads to the photooxidation of sterols. One of the photoproducts isolated is cholesterol-a-oxide (weakly carcinogenic), leading to the speculation that in vivo photooxidation might be the route for photocarcinogenesis.

Thus, lipid peroxidation affects a variety of cellular functions and may precede or be concurrent with other mechanisms leading to damage to the genetic material and cellular proteins.

It appears that lipid peroxide attached to the skin causes various kinds of cell damage, and leads to skin disease and skin tumors. Lipid peroxidation is considered at present to be one of the basic mechanisms involved in reversible and irreversible cell and tissue damage.

We will devote another section to the interaction of these lipid peroxides with other mediators derived from the uncontrolled oxidation of arachidonic acid and eicosapentanoic acid as part of the biochemical alterations inducing the inflammatory response.

Antioxidant systems and photooxidative stress

The skin is the major organ exposed to external radiation and thus is potentially affected by the action of free radicals and other ROS. Fortunately, different systems dealing with oxidative stress have evolved to maintain cellular integrity (32). In these elaborate systems, biologic antioxidants play a pivotal role. Even with these defense mechanisms, the requirements for the protection of the skin can be exceeded after considerable solar exposure. Actinic erythema is produced when the consumption of the antioxidants exceeds their regeneration, thereby affecting cellular functions.

Protection of the skin against these free radicals and reactive oxygen species can be achieved by 1) trapping the initial pro-oxidizing species, 2) sequestering heavy metals, preventing the initiating and propagating steps for the reactions producing free radicals, 3) trapping the secondary radicals that can propagate the chain reaction or reduce oxidized groups, and 4) repair of macromolecules and cell renovation.

The antioxidant systems that prevent free radical chain propagation by interrupting the initiation can be categorized as enzymatic systems, including superoxide dismutase (31), catalase (62), thioredoxin reductase (29), and several isoenzymes of glutathione peroxidase and glutathione reductase, the latter functioning to restore the levels of reduced glutathione. These enzymatic antioxidants mainly serve an intracellular function against oxidative stress, being absent or present in small amounts in the extracellular spaces. The organism also has a group of low molecular weight antioxidants which can be divided into lipid- and water-soluble molecules. ß-Carotene, a precursor of vitamin A, and a-tocopherol (vitamin E) are the main lipid-soluble non-enzymatic antioxidants and are mainly confined to cell membranes and low-density lipoprotein. Among water-soluble antioxidants, ascorbate is the most efficient antioxidant. Table 4 summarizes the most important characteristics of these systems.

Experimentally, the topical application of antioxidants has shown promising results in preventing damage and the photoinduced inflammatory response (63-66). Although melanin absorbs photons in the far UV and visible regions of the solar spectrum acting as a natural filter (67), it can also trap some of these reactive species and function as an antioxidant (40).

Biochemical alterations in the photoinduced erythema

The skin chromophores initiating the photochemical reaction that leads to the inflammatory response are unknown, but the outcome of these reactions results in erythema, edema, burning sensation and pain. Acute exposure of the skin to ultraviolet radiation induces the synthesis and liberation of eicosanoids (products derived from arachidonic acid), histamine, kinins, cytokines and other chemotactic factors (7), as well as the expression of adhesion molecules on the surface of epidermal and dermal cells. All these mediators activate endothelial cells in the dermis, increase vascular permeability and promote the accumulation of inflammatory cells 12 to 14 h after the injury. Natajaran (68) has recently noted that the effect of oxidants (ROS) on signal transduction in vascular endothelium is directly related to the pathogenesis of the inflammatory response. We will now turn to the discussion of the biochemical alterations that mediate the photoinduced erythema and the implication of the adhesion molecules relevant to the pathogenesis of the inflammatory response.

Biochemical mediators in the pathogenesis of erythema

Prostaglandins and other products derived from arachidonic acid

The eicosanoids are derived from arachidonic acid after activation of a phospholipase (69-71) and play an important role as mediators of the inflammatory response (72). The activation of this phospholipase is induced by lipid peroxidation (73). In vitro studies have demonstrated the activation of phospholipase A₂ and lysophospholipase (74,75) after UVB irradiation. The activation of phospholipases A₂ and C (76) has been suggested to occur before the increase in the synthesis of phosphorylcholine and eicosanoids after UVA irradiation. Both the nature of the eicosanoids and the levels they reach depend on the wavelength of the radiation (73,74). For example, cyclooxygenase inhibitors administered during the first 24 h after UVB exposure reduced by about 50% the severity of photoinduced erythema (77-80). However, indomethacin administered either topically or intradermally has no effect on erythema when the latter is induced only by UVA radiation (81).

Regarding the kinetics of the increase in their concentration, there is a fast release of prostaglandins (PG) E₂, F₂, D₂ and 12-R-HETE, even before the erythema has become clinically perceptible, and they persist for 48 h reaching a maximum level 18-24 h after exposure to UVB (14,73,77,82). In vitro studies have confirmed the dose-dependent increase in the levels of the released eicosanoids (65). Prostacyclin levels increase 5-9 h after irradiation and return to basal levels after 24-48 h (8,83). These results follow a similar pattern compared with the release of eicosanoids from keratinocytes and mast cells, supporting their role in the pathogenesis of UVB-induced erythema (84). The increase in PG E₂, D₂ and prostacyclin after UVA irradiation is also dose-dependent and reaches maximum levels 5-9 h after exposure. After 15 h, these substances begin to decrease and finally return to basal levels 24 h later (8). PG E₂ seems to be involved in the epidermal growth resulting from the exposure and increased vascular permeability (85) through the increase in leukotriene C4 levels. Nonetheless, leukotriene B4 also plays an important role in the chemotaxis of inflammatory cells (72,86).

Histamine

This mediator plays a very important role in the development of erythema (14,83,87,88). In vivo studies in humans have shown that mast cell degranulation occurs 4 h after skin irradiation (14,89), with histamine reaching maximal levels 9 to 15 h later and returning to basal levels after 24 h (8). Some authors (90-92) have shown that isolated mast cells can be stimulated to release histamine. This histamine release is of a noncytotoxic nature at low peroxidase concentrations, and the cells undergo cytotoxic reactions only at high peroxidase concentrations. It has also been shown (91) that H₂O₂ added exogenously or generated by the xanthine oxidase system activates mast cells for noncytotoxic histamine release. The agents released or generated from ROS during skin irradiation may act as degranulating or lytic substances on mast cells (91).

Neuropeptides

In vitro studies have shown that sun-induced inflammation may also be the result of primary stimuli of mediators other than histamine, including tachykinins and other families closely related to neuropeptides (93). In this regard, recognition of the similarity between sunburn pain and causalgia has suggested a new pathogenic approach implicating depletion of neuropeptides such as substance P (94).

Cytokines

Ultraviolet radiation promotes the release of pro-inflammatory cytokines from keratinocytes and other cells in the skin (e.g., interleukin (IL)-1, IL-3, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-a, transforming growth factor (TGF)-ß, GM-CSF, etc.) (95-98). All of these mediators seem to contribute to the formation of a special microenvironment for Langerhans cells and, subsequently, local UV-induced immunosuppression. In this regard, urocanic acid isomerization has been shown to induce TNF-a release and it has even been suggested that this mediator may be related to IL-10 (99). Furthermore, some of these cytokines (IL-1, IL-8) are also involved in the recruitment phase of the UV-induced inflammatory response due to their chemotactic activity (98,100), the former with a direct in vitro parallelism with PG E₂ levels, suggesting a possible connection between them (101).

Finally, in vivo and in vitro studies have implicated IL-1 (102,103) and IL-6 (104) in the general symptoms of the acute phase following excessive solar exposure, such as fever and leukocytosis.

Expression of adhesion molecules in UV-induced cutaneous

inflammation

The intercellular adhesion molecules (ICAM-1), endothelial adhesion molecules (E-selection or ELAM-1) and vascular adhesion molecules (VCAM-1) are regulated by cytokines, among other mediators, and implicated in the phenomenon of leukocyte adhesion (105). These cellular adhesion glycoproteins mediate the interaction between cells in the epidermis and dermis and those that are present in the infiltrate after diffusing from vascular walls (106). Therefore, these molecules seem to be crucial in the formation of the inflammatory infiltrate of actinic erythema.

Under normal conditions, ELAM-1 and VCAM-1 are minimally expressed but are induced by IL-1 and TNF (107). In vitro studies have shown their relationship with polymorphonuclear antibodies and monocytes but not with lymphocytes (108,109). Recently, Norris and coworkers (110) demonstrated that UVB radiation is an efficient stimulus for the expression of ELAM-1, reaching maximum levels 24 h after irradiation. Two mechanisms have been proposed for their induction: a) a direct stimulation of endothelial cells after absorption of photons in the UV region, or b) an indirect pathway mediated by IL-1 released from keratinocytes after the injury. Some similarities have been observed between the kinetics for the expression of ELAM-1 and the accumulation of inflammatory cells, showing that these surface molecules play an important role in the adhesion process for inflammatory cells.

Regarding other molecules involved in this inflammatory response, it has been observed that ultraviolet radiation can modulate the expression of ICAM-1 previously induced by the cytokines IL-1 and TNF (111,112). Cornelius and collaborators (113) have recently shown that UVB radiation directly upregulates the expression of ICAM-1 independently of IL-1 and TNF, a selectivity that has not been observed in the expression of ELAM-1 and VCAM-1.

In conclusion, it is conceivable that several manifestations of these reactions are induced by a direct action of photons on DNA and other chromophores and by generation of free radicals and other reactive oxygen species. Additionally, generation of prostaglandins, leukotrienes, histamine, cytokines and other mediators, as well as the expression of adhesion molecules may be involved in the inflammatory response. However, ongoing research exploring other mechanisms will ideally further our biochemical and biological understanding of actinic erythema.

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Address for correspondence: A.C. Tedesco, Departamento de Química, FFCL, USP, Av. Bandeirantes, 3900, 14040-901 Ribeirão Preto, SP, Brasil. Fax: 55 (016) 633-8151. E-mail: atedesco@usp.br

Research supported by FAPESP and CNPq. Received November 23, 1995. Accepted March 6, 1997.

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